RINGERS LACTATE VS NORMAL SALINE.pptx

COMPARATIVE STUDY OF NORMAL SALINE AND RINGERS LACTATE

1. INTRAVENOUS FLUID THERAPY: THE CASE OF NORMAL SALINE VS RINGERS LACTATE DR ANTHONY KWAW, RESIDENT PHARMACIST ACCIDENT AND EMERGENCY TAMALE TEACHING HOSPITAL TAMALE, GHANA Email: [email protected] 1

2. OUTLINE Introduction Comparative studies Myths on Ringers lactate use Specific indications for Ringers lactate Considerations for alternative IVF to Ringers lactate Practice Points Conclusion References 2

3. Patient Case Scenario  A 70-year-old-female is brought to the ED for altered mental status. The patient has had decreased PO intake over the last 3-4 days and fever and confusion that worsened in the last 24 hours. Her past medical history is significant for hypertension and coronary artery disease. Vitals are notable for a blood pressure of 82/44mmHg, HR of 118bpm, temperature of 39.1 C, RR of 14cpm, and SPO 2 96% on RA. The patient appears confused and dehydrated. Evaluation reveals a WBC of 24,000 mm 3 , lactate of 6.0mEq/L, K of 5.8mEq/L, and UTI on urinalysis. You have identified that the patient is in septic shock and requires fluid resuscitation. What fluid will you use to resuscitate your patient? What evidence will support that decision? Does the patients’ elevated lactic acid and potassium play a role in your choice of fluid? 3

4. Intravenous Fluids A 70kg adult requires 2-2.5L of fluids over 24 hours Losses are through urine (1.5L), stool (0.2L), and insensible losses (0.8L) This requirement is normally met through food (1000mL) and drink (1500mL). IVF are given if sufficient fluids cannot be given orally. Fluids are a standard treatment for various disease processes that present to the ED. 4

5. Intravenous Fluids Thought to increase intravascular and intracellular volume, fluids are critical in treatment of multiple disease processes that cause dehydration and loss of circulating fluid, leading to hypoperfusion and hypotension Historically, NS has been the fluid of choice for resuscitation Recent debate about preferred fluids based on composition in the treatment of various illnesses 5

6. The Composition of the Human Body 6

7. Water Content of the Body

8. Normal distribution of water ( Adults ) 8 For a 70kg man, total bodily fluid is ~42L (60% body weight); 36L in a 60kg adult ⅔ is intracellular (25-30L) and ⅓ is extracellular (13-16L). Of the extracellular compartment, ⅓ is intravascular, i.e. blood (5L) Lymph and transcellular fluid are 1.5L each

9. Normal distribution of water ( Infants ) 9 Water constitutes about 75-80% of the body weight. Solids constitute about 20 to 25% of the body weight. The total volume of water in an infant is about 3L The water in the intracellular compartment is ≈ 30% of the body weight. Water in the extracellular compartment constitutes 45% of the body weight. Plasma constitutes about 4% of the body weight of an infant

10. Types of Intravenous Fluids Dextrose 5%: Isotonic Small amount of glucose ~50g/L small energy (~10% daily energy per liter) liver rapidly metabolizes all the glucose leaving only water, which rapidly equilibrates throughout all fluid compartments. Not suitable for fluid resuscitation (only 1/9 will remain in the intravascular space), but suitable for maintaining hydration. Excess 5% glucose IV may lead to water overload and hyponatremia Dextrose 10% and 50% Hypertonic Used to correct hypoglycemia 10

11. Types of Intravenous Fluids Dextrose in Sodium chloride Required for fluid maintenance 1/5 Dextrose in 0.18% Sodium chloride used in pediatric setting 5 % Dextrose in 0.9% Sodium chloride used in adult patients Colloids (e.g. Gelofusine ) Have a high osmotic content similar to that of plasma and therefore remain in the intravascular space for longer than other fluids, making them appropriate for fluid resuscitation, but not for general hydration. Colloids are expensive, and may cause anaphylactic reactions. In reality, effective fluid resuscitation will use a combination of colloid and 0.9% saline 11

12. Types of Intravenous Fluids Sodium chloride 0.9% About the same Na+ content as plasma (150mmol/L) and is isotonic with plasma. Equilibrate rapidly throughout the extracellular compartment only, but takes longer to reach the intracellular compartment than 5% glucose. Appropriate for fluid resuscitation, as it remains predominantly in the extracellular space Also for maintaining hydration Ringers lactate Considered more physiological due to the similarity in its composition compared to human plasma Less risk of causing acidosis compared to NS 12

13. IVF COMPOSITION Contents Human plasma NS RL Plasma- lyte A Sodium ( mEq /L) 135-145 150 130 140 Potassium ( mEq /L) 4.5-5.0 4 5 Chloride ( mEq /L) 94-111 154 109 98 Calcium ( mEq /L) 2.2-2,6 2.7 Magnesium ( mEq /L) 0.8-1.0 3 Bicarbonate ( mEq /L) 23-27 Lactate ( mEq /L) 1-2 28 Acetate ( mEq /L) 27 Gluconate ( mEq /L) 23 pH 7.4 5.5 6.5 7.4 13 NS has relatively more chloride than human plasma; risk of hyperchloremic metabolic acidosis This may delay recovery in some disease process and may contribute to worsening renal function during treatment Elevated chloride causes renal vasoconstriction and may decrease renal perfusion via this mechanism

14. COMPARATIVE STUDIES 14

15. Saline Against Lactated ringers or Plasma- Lyte in the Emergency Department (SALT-ED) Trial (Wesley et al ., 2018) An RCT conducted in 2016 (over 16 months) to compare NS and balanced crystalloids in non-critically ill patients (n= 13,347) A single-center, pragmatic, multiple-crossover trial Trial evaluated hospital-free days (days alive after discharge before day 28) as well as major adverse kidney events within 30 days composite of death from any cause new renal replacement therapy persistent renal dysfunction with creatinine >200% from baseline 15

16. SALT-ED TRIAL- Outcome 16 Primary outcome of hospital-free days did not have a significant difference between NS and balanced crystalloid groups Significantly lower rate of adverse major kidney events in 30 days between balanced crystalloid and NS groups (4.7% vs. 5.6%) Patients in the balanced crystalloid arm showed lower chloride and higher bicarbonate concentrations persisting for several days into hospitalization. Patients with underlying renal dysfunction or hypochloremia at presentation appeared to have the largest benefit from the balanced crystalloid therapy by having reduced incidents of major adverse kidney events in 30 days

17. Isotonic Solutions and Major Adverse Renal Events Trial (SMART) (Semler et al., 2018) An RCT conducted in 2016 (over 16 months) to compare NS and balanced crystalloids in critically ill patients (n= 15,802) A pragmatic, cluster-randomized, multiple-crossover trial The primary outcome was a major adverse kidney event within 30 days composite of death from any cause new renal replacement therapy persistent renal dysfunction with creatinine >200% from baseline 17

18. SMART TRIAL- Outcome Significant decrease in major adverse kidney events within 30 days for balanced crystalloids vs NS (14.3%% vs 15.4%, p=0.04) Insignificant decrease in in-hospital mortality at 30 days for the balanced crystalloid vs. NS group (10.3% vs 11.1%, p=0.06). Similarly, the balanced crystalloid group showed lower incidence of hyperchloremia defined as Cl > 110 mmol/L (24.5% VS 35.6%) and lower incidence of plasma bicarbonate concentration < 20 mmol/L (35.2% vs. 42.1%) when compared to NS. 18

19. SMART TRIAL- Outcome The incidence of new renal-replacement therapy for the balanced crystalloid vs. NS group was 2.5% and 2.9%, respectively (P=0.08) The incidence of persistent renal dysfunction for the balanced crystalloid vs. NS group was 6.4% and 6.6%, respectively (P=0.60). 19

20. SMART TRIAL- Outcome Importantly, patients with a diagnosis of sepsis had lower incidence of 30-day mortality in the balanced crystalloid vs. NS groups (25.2% vs 29.4%, p=0.02). This is also important because fluids are a key treatment in sepsis and volume of fluid resuscitation is often higher.. Based on these results, 1 in every 94 patients admitted to the ICU and treated with balanced crystalloid instead of NS may prevent the need for new renal replacement therapy, persistent renal dysfunction, or death when compared to NS 20

21. SALT-ED + SMART 21 These two RCTs are groundbreaking and practice changing, leading many emergency departments and intensive care units to transition to more regularly using balanced crystalloids over NS. While conclusions of the trials often point to RL being superior to NS, it can also be reassuring that NS was given to so many patients without substantial harm.

22. What if……..? 22 The volume of IVF administered in this studies may be more important than the specific type of fluid i.e. worse outcomes with excess IVF

23. Balanced Solution versus Saline in Intensive Care Study ( BaSICS Trial) ( Zampieri et al., 2021) 23 A robust RCT that compares plasma- lyte with normal saline for fluid resuscitation in the ICU and two rates of fluid administration, 999 ml/ hr and 333 ml/ hr (n=11,000) A multicenter, double blind RCT from 75 ICUs across Brazil Primary outcome was a 90-day mortality rate between fluid type and rate of IVF infusion

24. BaSICS Trial-Outcome 24 90-day mortality rate was; 26.4% in the plasma- lyte group and 27.2% in the NS group ( aHR 0.97, CI 0.90-1.05, P=0.47) 26.6% in the slower infusion rate vs 27.0% in the faster infusion rate group ( aHR , 1.03; 95% CI, 0.96-1.11; P=0.46). A secondary outcome from the BaSICS trial showed no significant difference in need for renal replacement therapy or doubled creatinine in balanced crystalloid group (27.8%) versus NS group (28.9%) (95% CI, 0.86-1.04, p=0.37)

25. Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis Trial (CLOVERS TRIAL) 25 The idea of “you have to swell to get well” is no longer the standard of care, and permissive hypotension is preferred in several disease states. CLOVERS seeks to compare early transition from fluids to vasopressors in patients with septic shock and also answer important question about fluid volume and rate or volume given to patients during resuscitation A multicenter, randomized, un-blinded, two-arm clinical trial to determine the impact of a restrictive fluids (“Medicine to Raise Blood Pressure First”) strategy as compared with a liberal fluids (“Fluids First”) strategy on 90-day in-hospital mortality (n=2,320)

26. Update on CLOVERS Trial Phase 3 stopped in February, 2022 No significant difference observed between the two arms in the first 24 hours of treatment (n=1,566) No significant difference in 90-day mortality rates nor safety concerns They will continue patient follow-up according to the study protocol for those already enrolled in the trial Conducted by the PETAL Network and sponsored by NHLBI 26

27. RL or NS? 27 BaSICS trial makes it clear that there is not one fluid that is ideal, and certain populations and diseases will benefit from selected fluid choice SALT-ED and SMART trials showed that both non-critically ill and critically ill patients who received balanced crystalloids were less likely to have renal injury leading to need for renal replacement therapy or to have persistent renal dysfunction, but an additional large ICU based RCT ( BaSICS Trial) did not show statistical difference in balanced crystalloid versus NS. Fluid therapy should be targeted to specific patient populations and presenting disease.  

28. Myths surrounding Ringers lactate!!! Despite these studies, there are still several concerns regarding the use of RL in the ED 28

29. 1. Hyperkalemia Myth – “Ringers lactate should not be used in hyperkalemia because it contains potassium and may make the problem worse.” Hyperkalemia is the electrolyte abnormality most likely to quickly kill a patient Causes; Drugs (Co- trimixazole , ACEIs, ARBs, Potassium-sparing diuretics etc.) Rhabdomyolysis Cell death Though Ringers lactate contain a higher concentration of potassium (4mEq/L) when compared to NS (0 mEq /L), its potassium composition is physiologically closest to human serum (4.5-5.0mEq/L) and is typically slightly lower 29

30. Hyperkalemia There is negligible effect on overall serum potassium level as a result of RL infusion since potassium’s volume of distribution is greater in extracellular fluid causing little to no change on the overall serum potassium level. It would take a significant amount of fluid to have any effect on raising overall serum potassium level since the potassium equilibrates between intracellular and extracellular fluid spaces. Hyperchloremic metabolic acidosis which can result from NS infusion will increase cellular shifting and worsen extracellular potassium levels when compared to RL which has no effect on the K+/H+ gradient. Alkalinization that occurs as a result of RL infusion due to the 28 mEq /L of lacatate may even further drive potassium into the cell, lowering the overall serum potassium level. 30

31. Hyperkalemia One subgroup analysis from the SMART trial evaluated critically ill adults with hyperkalemia who received balanced crystalloids RL or plasma- lyte vs. NS. Overall, 8 (8.5%) of the patients in the balanced crystalloid group vs. 13 (14.0%) patients in the NS group developed severe hyperkalemia (p=0.24). While this is not statistically significant, it does show that the higher level of potassium that is administered from RL or plasma- lyte (4-5) vs. NS (0) is closer to physiologic plasma and does not lead to worsening hyperkalemia. 31

32. Hyperkalemia Pearl: RL is a safe fluid to use in resuscitation of patients with elevated potassium levels. The potassium/hydrogen shifts that occur as result of the acidic environment from normal saline infusion may worsen serum potassium levels. 32

33. 2. Lactic acidosis Myth – “ Ringers lactate causes lactic acidosis, and therefore should be avoided.” Lactic acidosis is a result of failed oxidative metabolism, leading to an anion-gap metabolic acidosis. This can be secondary to decreased metabolism of naturally generated lactate in the body (such as in liver disease) or increased production of lactate when there is decreased oxygen available for aerobic metabolism. Causes; sepsis, trauma dehydration. iatrogenic causes of type B lactic acidosis secondary to beta agonist administration, such as epinephrine or albuterol (less common) 33

34. Lactic acidosis 34 The lactate in RL is in the form of sodium lactate which our bodies metabolize to products that prevent cellular death. It is not the same lactate that is generated during anaerobic metabolism, which causes metabolic acidosis ( Robergs et al., 2017) One double-blind RCT evaluated the change in lactate between RL and NS groups while also looking at the overall change in pH, bicarbonate, sodium, and chloride levels. This study found that after an infusion of 30mL/kg IV RL, lactate increased by 0.93 mmol/L compared to 0.37 mmol/L in the NS group (p=0.2), but the NS group saw a larger decline in overall pH (0.06 vs. 0.03) and bicarbonate level (2.35 vs. 0.36) ( Zitek et al., 2018)

35. Lactic acidosis 35 In an additional RCT published by Didwania et al. (1997), 24 healthy adults received 1L infusions of RL, NS, dextrose, or D5W and showed no difference in lactate levels post-infusion It is theorized that the lactate infused in the RL group may be metabolized under ischemic conditions and decrease overall cell death and is less likely to worsen an acidosis when compared to the hyperchloremic acidosis that results from NS. Pearl: Though RL contains sodium lactate, this is generally metabolized by the body and does not contribute to worsening lactic acidosis. In fact, the acidosis associated with NS likely has more clinically harmful effects.

36. 3. Medication Reactions 36 Some Truth – “Because ringers lactate can have calcium precipitation with so many medications, it is easier and safer to use normal saline.” It is postulated that the sodium concentration within ceftriaxone contributes to the formation of calcium precipitates and therefore the mixture of these solutions in the same line should be avoided.  An additional study evaluated compatibility of RL with 94 medications by in vitro visual observation, particle counting testing, and light obscuration particle count testing. Eight drugs were considered incompatible with RL including ciprofloxacin, cyclosporine, diazepam, ketamine, lorazepam, nitroglycerin, phenytoin, and propofol and are recommended against administering through the same IV line as RL (Vallee et al., 2021)

37. Medication Reactions 37 Two separate studies were performed to evaluate the incidence of clot formation when RL was transfused with packed RBCs and Whole Blood. In both studies, there was no statistically significant difference in clot formation when NS or RL was infused or used as a diluent in emergent transfusions. There is however, a theoretical risk of coagulation when RL is administered together with preserved blood (with citrate anticoagulant) via the same infusion set (Singh et al, 2021; Lorenzo et al., 1998; Cull et al., 1991)

38. Medication Reactions 38 Pearl: Though theoretical risk of clotting exists, RL can be administered simultaneously in patients >28 days with ceftriaxone, blood products and other calcium-containing medications. If possible, a separate line should be used to avoid potential precipitation.

39. SPECIFIC INDICATIONS FOR RINGERS LACTATE 39

40. 1. Diabetic Ketoacidosis (DKA) In DKA, the body responds to low insulin levels by burning fatty acids and producing ketone bodies, leading to an anion-gap metabolic acidosis. Often overall body potassium is low; however, it may appear to be falsely elevated due to hydrogen ions shifting intracellularly and potassium moving extracellularly. Fluids, in addition to insulin and potassium, are the main treatment for this disease process 40

41. Diabetic Ketoacidosis (DKA) One subgroup analysis from the SALT-ED and SMART trial compared patients with a clinical diagnosis of DKA to look at; time to resolution (glucose <200 mg/dL) 2 of the following: bicarb > 15, venous pH >7.3, anion gap ≤ 12) time to discontinuation of insulin infusion. Given the sheer volume of fluid required to treat this disease process, (on average, 4.5 liters) differences in fluid composition can be a key factor in recovery. 41

42. Diabetic Ketoacidosis (DKA) 42 Outcome significant decrease in both time to resolution of DKA (13 hours vs 16.9 hours) in the balanced crystalloid group as well as time to insulin discontinuation (9.8 hours vs 13.4 hours). This equates to an absolute reduction of 4 hours and relative reduction of 20-30% in time to DKA resolution and discontinuation of insulin infusion, possibly decreasing overall hospital stay and associated morbidity. This is hypothesized to be due to the concentrations of sodium lactate in RL and acetate in plasma- lyte which metabolize into bicarbonate helping to close the anion gap metabolic acidosis.

43. Diabetic Ketoacidosis (DKA) Additionally, fewer patients in the balanced crystalloid group exhibited hypokalemia ( K + < 3mmol/L) compared with the NS group. However, this study was in contrast to prior work on the subject which failed to show any significant difference (Self et al., 2017; Mahler et al. , 2011; Van Zyl et al., 2012; Jayashree et al., 2019; Yung et al., 2017) 43

44. 2. Dehydration In patients with dehydration (defined as dry mucous membranes, SBP <90 mmHg, HR >100 bpm or PO intolerance), a RCT comparing NS and balanced crystalloids showed significantly lower pH levels in patients who received NS (7.40 7.37 7.36) as well as a drop in bicarbonate levels (23.1, 22.2, 21.5) compared to an increase in the plasma- lyte group (7.40 7.42 7.45) and (23.4, 23.9, 24.4) ( Hasman et al., 2012) A similar study conducted in pediatric patients with acute diarrhea and severe dehydration showed no significant difference in pH between NS and RL, but the RL group required less fluids (310 vs 530mL) and had a shorter median hospital stay (38 vs 51 days) (Mahajan et al., 2012) 44

45. 3. Pancreatitis One RCT compared RL with NS in patients with acute pancreatitis and found a significant reduction in SIRS after 24 hours in the RL group (84% vs 0%, p=0.035). There was also a reduction in CRP in the RL group (51.5 vs 104, p=0.02), a marker of systemic inflammation (Wu et al., 2011) An additional study by Lee et al . (2021) showed that there was a significantly shorter hospital length of stay and fewer ICU admissions in patients diagnosed with acute pancreatitis who were treated with aggressive fluid resuscitation via RL compared to NS Though the exact mechanism is unknown, there are animal studies showing decrease in enzymes involved in pancreatitis such as zymogen ( Khatua et al., 2020) Pearl: Several studies shows balanced crystalloids are associated with improved outcomes in patients with DKA, dehydration, and pancreatitis. 45

46. INTERLUDE 1 Corinthians 10:23 ALL THINGS ARE LAWFUL FOR ME, BUT ALL THINGS ARE NOT EXPEDIENT… (KJV) 46

47. CONSIDERATIONS FOR ALTERNATIVE FLUID TO RINGERS LACTATE 47

48. 1. Traumatic brain injury It is theorized that due to hyperosmolarity of the solution and ability to decrease cerebral edema, NS is the preferred resuscitation fluid in patients with Traumatic Brain Injuries (TBI) when compared with RL Additionally, RL is thought to increase neutrophil and inflammatory responses. One study comparing outcomes of patients with TBI who were treated with RL vs NS prior to hospital arrival found RL was associated with higher 30-day mortality than NS (HR = 1.78, CI 1.04 – 3.04, p=0.03) (Rowell et al., 2016) Subgroup analysis on this topic with the best RCT to date, BaSICS Trial, showed that a balanced crystalloid (plasma- lyte ) had higher 90-day mortality rate (31.3%) versus NS (21.1%) (HR 1.48, 95% CI 1.03-2.12, p=0.02) ( Zampieri et al., 2021) 48

49. 2. Hyponatremia RL contains 130 mEq /L Na compared to 135-145mEq/L Na in plasma. Because of this, there is concern that resuscitation with RL may worsen or lead to hyponatremia. There is limited data around RL causing hyponatremia or the use of RL in treating acute hypovolemic hyponatremia in the Emergency Department setting. One study evaluated post-operative hyponatremia and cited quantity of fluid resuscitation as the cause of hyponatremia versus use of RL itself. The theory is that increased extracellular volume leads to ADH release and worsens hyponatremia. (Steele et al., 1997) 49

50. 3. Burns 50 In acute burns, there is concern for both dehydration and electrolyte imbalances such as hyponatremia and hypoglycemia secondary to evaporative losses and changes in cellular permeability. One RCT evaluated the use of RL alone in burn resuscitation when compared to use of RL and Dextrose in NS in an attempt to correct electrolyte abnormalities. This study showed that due to low sodium (130mEq/L) and potassium (4mEq/L) levels in RL when compared to human plasma, dextrose containing NS should be used as an adjunct to assist in replenishing electrolytes.

51. 3. Burns Burn patients treated with RL and DNS had statistically significant less evidence of hyponatremia and hypoglycemia ( Bedi et al ., 2019) Pearl: In patients presenting with hyponatremia and acute burns, RL is not necessarily the sole fluid choice for resuscitation, and NS is preferred in patients with concern for TBI. 51

52. Practice Points Ringers lactate composition is more similar to human plasma than Normal saline Ringers lactate is preferred to Normal saline in select ED presentations, such as DKA, dehydration and pancreatitis Ringers lactate will not worsen hyperkalemia and the acidosis but Normal saline may in fact be more detrimental 52

53. Practice Points Ringers lactate does contain sodium lactate but will not contribute to clinically significant worsening lactic acidosis Normal saline  is preferred in patients with TBI. Consider Normal saline when mixed with certain medications such as ceftriaxone or blood transfusions to avoid precipitation when only a single IV access site it available 53

54. Patient Case Scenario The 70-year-old female is febrile with signs of dehydration and hypotension in the setting of sepsis due to a urinary tract infection. She also has lactic acidosis and hyperkalemia on her initial workup. Based on the data above, RL is a safe and appropriate approach to fluid resuscitation in combination with antibiotics. Broad spectrum antibiotics should be started and the patient admitted to the medical ICU for further workup and care. 54

55. CONCLUSION No single IVF is superior to the other and the choice should be based on the clinical condition Use of Ringers lactate in most cases has better outcomes compared to the use of NS RL should be the first line IVF for resuscitation in some selected indications 55

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64. REFERENCES Robergs et al. (2017). Lactate, not Lactic Acid, is Produced byCellular Cytosolic Energy Catabolism. PHYSIOLOGY 33: 10–12. doi:10.1152/physiol.00033. 64

65. ACKNOWLEDGEMENT Dr Amos Adapalala Bugri (Senior Specialist Pharmacist) 65

66. THANK YOU 66